- Regulation of xanthine oxidase activity by substrates at active sites via cooperative interactions between catalytic subunits: Implication to drug pharmacokinetics
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Three xanthine oxidase substrates (i.e., xanthine, adenine, and 2-amino-4-hydroxypterin) show a "substrate inhibition" pattern (i.e., slower turnover rates at higher substrate concentrations), whereas another two substrates (i.e., xanthopterin and lumazine) show a "substrate activation" pattern (i.e., higher turnover rates at higher substrate concentrations). Binding of a 6-formylpterin at one of the two xanthine oxidase active sites slows down the turnover rate of xanthine at the adjacent active site from 17.0 s-1 to 10.5 s-1, and converts the V-[S] plot from "substrate inhibition" pattern to a classical Michaelis-Menten hyperbolic saturation pattern. In contrast, binding of xanthine at an active site accelerates the turnover rate of 6-formylpterin at the neighboring active site. The experimental results demonstrate that a substrate can regulate the activity of xanthine oxidase via binding at the active sites; or a xanthine oxidase catalytic subunit can simultaneously serve as a regulatory unit. Theoretical simulation based on the velocity equation derived from the extended Michaelis-Menten model shows that the substrate inhibition and the substrate activation behavior in the V-[S] plots could be obtained by introducing cooperative interactions between two catalytic subunits in homodimeric enzymes. The current work confirms that there exist very strong cooperative interactions between the two catalytic subunits of xanthine oxidase.
- Tai,Hwang
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- One-Step Synthesis of 2-Fluoroadenine Using Hydrogen Fluoride Pyridine in a Continuous Flow Operation
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We report the development of a one-pot synthesis of 2-fluoroadenine from an inexpensive 2,6-diaminopurine starting material using diazonium chemistry in a continuous fashion. Given the sensitivity of this transformation to temperature, we conducted critical experiments to study the exothermicity of the reaction and the heat removal, which were critical for the development of the process. Our goal was to improve the yield and purity of this pharmaceutical intermediate (2-fluoroadenine) and develop a more robust process.
- Salehi Marzijarani, Nastaran,Snead, David R.,McMullen, Jonathan P.,Lévesque, Fran?ois,Weisel, Mark,Varsolona, Richard J.,Lam, Yu-Hong,Liu, Zhijian,Naber, John R.
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supporting information
p. 1522 - 1528
(2019/07/10)
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- Preparation of the 2′-deoxynucleosides of 2,6-diaminopurine and isoguanine by direct glycosylation
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Chemical Equetion Presentation The purine nucleoside 2,6-diaminopurine- 2′-deoxyriboside is prepared by the direct glycosylation of the 2,6-bis(tetramethylsuccinimide) derivative of the parent purine heterocycle 4 with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranosyl chloride 5 using the sodium salt method. 2′-Deoxyisoguanosine is prepared from 2,6-diaminopurine by a five-step procedure. The purine heterocycle isoguanine is prepared by selective diazotization of 2,6-diaminopurine and then converted to the N9-trityl derivative to increase solubility. After silylation of the O 2-carbonyl with TMSCl, the N6-amino group is protected as the tetramethylsuccinimide (M4SI). The O2-carbonyl is protected as the DPC derivative, and the trityl group is removed. The resulting product is glycosylated in good yield to generate fully protected 2′-deoxyisoguanosine.
- Arico, Joseph W.,Calhoun, Amy K.,McLaughlin, Larry W.
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experimental part
p. 1360 - 1365
(2010/04/30)
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- Purines. LXXIX. Synthesis and hydrolysis of 3-methoxyadenine and its N6-benzyl derivative leading to the corresponding 2-hydroxyadenines
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Methylation of adenine 3-oxide (8a) with MeI in AcNMe2 afforded 3- methoxyadenine (9a) in 44% yield. This compound (9a) underwent hydroxide-ion attack at the 2-position to give 2-hydroxyadenine (isoguanine) (10a) in 38% yield. A parallel reaction sequence starting from N6-benzyladenine 3-oxide (8c) and proceeding through N6-benzyl-3-methoxyadenine (9c) provided N6- benzyl-2-hydroxyadenine (10c) in 29% overall yield, together with a small amount of N6-benzyladenine (11c).
- Itaya, Taisuke,Kanai, Tae,Takada, Yasutaka,Kaneko, Miki,Yasuhara, Kensuke,Fujii, Tozo
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p. 554 - 556
(2007/10/03)
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- Oligonucleotides containing consecutive 2'-deoxyisoguanosine residues: Synthesis, duplexes with parallel chain orientation, and aggregation
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The 2'-deoxyisoguanosine phosphonates 3a and 4a and the phosphoramidites 3b and 4b were prepared as building blocks for solid-phase oligonucleotide synthesis. The diphenylcarbamoyl (dpc) residue was introduced as 2-oxo protecting group which stabilizes the N-glycosylic bond against hydrolysis and prevents the molecule from side reactions. The dpc-protected building blocks 4a,b were employed in solid-phase synthesis and were found to be much more efficient than the unprotected compounds 3a,b. Oligonucleotides with alternating (11) or consecutive isoguanine residues (13-15) were synthesized. They form duplexes with parallel chain orientation. The aggregate d(T4-iG4-T4) (15) containing four consecutive 2'-deoxyisoguanosine is shown to be a tetramer similar to that of d(T4-G4-T4).
- Seela,Wei
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- A NOVEL AND EFFICIENT SYNTHESIS OF ISOGUANOSINE
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Isoguanosine (4b) was synthesized by a one-pot reaction involving a condensation of 5-amino-1-(β-D-ribofuranosyl)imidazole-4-carboxamide (1b) with benzoyl isothiocyanate, treatment of the resulting thiourea derivative with DCC furnished 5-(N1-benzoylcarbamoyl)aminoimidazole-4-carbonitrile (3b) which was then annulated with ethanolic ammonia to afford isoguanosine in a 68percent yield from 1b.
- Chern, Ji-Wang,Lee, Horng-Yuh,Huang, Min,Shish, Fang-Jy
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p. 2151 - 2154
(2007/10/02)
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- RING OPENING AND CLOSING REACTIONS OF IMIDAZOLES AND OTHER 1,3-DIAZAHETEROCYCLES WITH VINYL CHLOROFORMATE AND PHENYL CHLOROFORMATE
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Treatment of imidazole and benzimidazole with vinyl chloroformate or phenyl chloroformate in weakly alkaline aqueous solution leads to their conversion into the corresponding imidazol-2-ones; in weakly acidic solutions these chloroformates convert adenine into isoquanine, 6-methylaminopurine into 1-methylisoquanine and pyrimidine into an acyclic product.
- Pratt, R. F.,Kraus, K. K.
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p. 2431 - 2434
(2007/10/02)
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